Project Summary /Abstract Activation of RAGE (receptor of advanced glycation endproducts (AGEs)), via binding of AGEs and other ligands, modulates the development and progression of diabetic complications through persistent and cyclic activation of nuclear factor-?B. Targeting RAGE directly as a therapeutic strategy has largely been unsuccessful. However, RAGE signaling can be interrupted, in vivo, by ADAM10 (a disintegrin and metalloproteinase 10) directed proteolytic cleavage of the RAGE ectodomain, and thus creating a soluble isoform of RAGE (sRAGE) that is released from the cell and appears into the circulation. Maintaining high levels of circulating sRAGE is advantageous as sRAGE will sequester RAGE ligands and prevent RAGE cell signaling. Our long-term goal is to identify strategies for the prevention and treatment of diabetic complications. Using aerobic exercise, we have elucidated a mechanism for ADAM10 upregulation to increase RAGE shedding. Aerobic exercise presents a unique model for mechanistic study of RAGE shedding as muscle contraction provides stimuli for tissue remodeling and resolution of the metabolic milieu that drives inflammation. Our central hypothesis is that skeletal muscle is a quantitatively important source of sRAGE appearance in the circulation and maintenance of healthy levels of total sRAGE promotes cardiometabolic health. The rationale is that once the mechanisms of ADAM10 activation and sRAGE generation are elucidated, progress towards the prevention and treatment of diabetic complications may be possible. Compelled by noteworthy preliminary data, we propose three specific aims to pursue our central hypothesis: (1) we will test the effects of acute and chronic exercise in generating sRAGE isoforms (2) we will determine the effects of acitretin therapy on RAGE mediated inflammation and (3) we will explore new protective effects of sRAGE in the microvasculature. The work is innovative because the study of RAGE ectodomain shedding in human skeletal muscle challenges the current understanding of AGE/RAGE biology and the known behavior of ADAM10 activity. At the completion of these studies, it is our expectation that we will have identified a novel mechanism of ADAM10 activation and an important tissue source of sRAGE production. Ultimately, such an insight has the potential to improve the prevention and therapeutic management of diabetes and its complications, thus reducing the financial and social burden that affects the ~347 million people worldwide with diabetes.